* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference：
[1] Journal of the American Chemical Society, 2018, vol. 140, # 32, p. 10140 - 10144
2
[ 3058-39-7 ]
[ 100-20-9 ]
[ 6068-72-0 ]
[ 1711-02-0 ]
Reference：
[1] Journal of the American Chemical Society, 2018, vol. 140, # 32, p. 10140 - 10144
3
[ 288-32-4 ]
[ 3058-39-7 ]
[ 25372-03-6 ]
Yield
Reaction Conditions
Operation in experiment
98%
With copper(l) iodide; caesium carbonate; dimethylbiguanide In N,N-dimethyl-formamide at 20 - 110℃; for 8.16667 h;
General procedure: A 25 mL flask with a magnetic stirring bar was charged with CuI(9.6 mg, 0.05 mmol), metformin (0.1 mmol), Cs2CO3 (652 mg,2.0 mmol), imidazole (1.0 mmol), an aryl halide (1.1 mmol), andDMF (5 mL). The mixture was stirred for 10 min at room temperature,and then heated to 110∘C for the appropriate amount of time(see Table 2). The progress of the reaction was monitored by TLC.After completion of the reaction, the mixture was extracted with EtOAc (5 1 mL) and the organic phase separated and evaporated. Further purification by column chromatography gave the desired coupled product.
95%
With copper(I) oxide; caesium carbonate In N,N-dimethyl-formamide at 120℃; for 12 h;
General procedure: A 10-mL vial was charged with aryl halide (0.5 mmol), Cs2CO3 (1 mmol), Cu2O (0.05 mmol), N-containing heterocycles (0.75 mmol), DMF (1 mL), and a magnetic stir bar. The mixture was stirred at 120 °C (130 °C for entry 19). The reaction mixture was held at this temperature for 12 h (24 h for entry 18, 20, 21, and 25). After allowing the mixture to cool to room temperature, the reaction mixture was extracted with ethyl acetate (3 10 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate/petroleum ether as the eluent) to provide the target products 3a–3t.
93%
With C40H34CuIN6O6; sodium hydroxide In dimethyl sulfoxide at 100℃; for 4 h; Sealed tube
General procedure: For the catalysis reaction, the catalyst C1 (12 mg,0.01 mmol), imidazole (1.0 mmol), aryl halide(1.0 mmol), NaOH (80 mg, 2.0 mmol), and dimethylsulfoxide (DMSO, 5 mL) were taken in a sealed tube. The reaction mixture was stirred at 100 °C for 4 h and then cooled to room temperature. After adding 5 mL of H2O, the solution was extracted with ethyl acetate. The organic layer was then dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure.The N-arylated product was finally obtained by columnchromatography on silica gel.
91%
With copper(l) iodide; 1,10-phenanthroline N-oxide; caesium carbonate In N,N-dimethyl-formamide at 20℃; for 22 h; Inert atmosphere
To the three-neck flask, CuI (19 mg, 0.1 mmol, 10 molpercent), 1,10-phenanthroline-N-oxide (39 mg, 0.2 mmol, 20 molpercent), Cs2CO3 (650 mg, 2.0mmol). The reaction flask was evacuated under argon. p-cyanoiodobenzene (229 mg, 1.0 mmol), imidazole (102 mg, 1.5 mmol) and DMF (2 ml) were added under argon atmosphere. The reaction was allowed to proceed at room temperature for 22 hours until the reaction starting material was completely reacted (TLC assay reaction was complete). After completion of the reaction, a brown oil was obtained which was diluted with ethyl acetate. The inorganic salt was removed by filtration and the solvent was removed by rotary evaporation. The residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate as eluant to give 1-(4-carbonitrilephenyl)imidazole as a white solid in 91percent yield.
96%Chromat.
With C16H12ClN3OPdS; potassium hydroxide In dimethyl sulfoxide at 110℃; for 10 h;
General procedure: Arylhalide (1.0 mM), nitrogen-containing heterocycle (1.2 mM), KOH (2 mM), and the catalyst (0.75 Mpercent) were stirred in dimethyl sulfoxide (DMSO) (4 mL) at 110 °C for 10 h. After completion of the reaction, the mixture was cooled to room temperature, diluted with ethyl acetate (10 mL) and filtered. The filtrate was concentrated and the residue was purified by column chromatography on silica gel using hexane/ethyl acetate(70 : 30) as eluent to afford the desired product. The products have been characterized by 1H NMR spectroscopy.
Reference：
[1] Tetrahedron Letters, 2013, vol. 54, # 52, p. 7095 - 7099
[2] Synthetic Communications, 2017, vol. 47, # 19, p. 1797 - 1803
[3] Synlett, 2004, # 1, p. 128 - 130
[4] Journal of Organic Chemistry, 2005, vol. 70, # 13, p. 5164 - 5173
[5] Indian Journal of Chemistry - Section A Inorganic, Physical, Theoretical and Analytical Chemistry, 2018, vol. 57A, # 2, p. 181 - 185
[6] New Journal of Chemistry, 2015, vol. 39, # 4, p. 2901 - 2907
[7] Patent: CN104356131, 2016, B, . Location in patent: Paragraph 0145-0156
[8] Journal of Coordination Chemistry, 2015, vol. 68, # 19, p. 3537 - 3550
[9] Catalysis Science and Technology, 2017, vol. 7, # 19, p. 4401 - 4412
4
[ 288-13-1 ]
[ 3058-39-7 ]
[ 25699-83-6 ]
Reference：
[1] Chemistry - A European Journal, 2014, vol. 20, # 18, p. 5231 - 5236
[2] Catalysis Science and Technology, 2017, vol. 7, # 19, p. 4401 - 4412
5
[ 3058-39-7 ]
[ 49584-26-1 ]
Reference：
[1] Journal of Organic Chemistry, 2003, vol. 68, # 21, p. 8274 - 8276
6
[ 109-01-3 ]
[ 3058-39-7 ]
[ 34334-28-6 ]
Reference：
[1] European Journal of Organic Chemistry, 2015, vol. 2015, # 19, p. 4153 - 4161
7
[ 64-17-5 ]
[ 3058-39-7 ]
[ 13939-06-5 ]
[ 7153-22-2 ]
Yield
Reaction Conditions
Operation in experiment
69%
With C35H20F34NO3(1-)*Pd(2+)*Cl(1-); N-ethyl-N,N-diisopropylamine In neat (no solvent) at 130℃; for 0.25 h; Microwave irradiation
General procedure: A mixture of the aryl halide (1.0 mmol), alcohol (5.0 equiv), Mo(CO)6 (0.5 equiv), DIPEA (1.5 equiv) and palladacycle 1 (1 mol percent Pd) was heated in a pressure tube at 130 °C under microwave irradiation. The reaction was monitored by TLC. When the reaction has completed, the reaction mixture was cooled to room temperature and the alcohol was removed. The crude mixture was subjected to F-SPE to remove palladacycle 1 (see general procedure for the recycling of palladacycle 1) and the solution of crude product was concentrated, diluted with EtOAc (20 mL) and washed successively with 2 M HCl (210 mL) and water (10 mL). The organic layer was driedover anhydrous MgSO4, filtered and concentrated to give pure 6.
Reference：
[1] Green Chemistry, 2016, vol. 18, # 17, p. 4649 - 4656
17
[ 64-17-5 ]
[ 623-00-7 ]
[ 3058-39-7 ]
[ 51934-41-9 ]
Yield
Reaction Conditions
Operation in experiment
80%
at 110℃; for 30 h; Schlenk technique; Inert atmosphere; Sealed tube
General procedure: A Schlenk tube was charged with Cu2O (7.2 mg, 10 molpercent), l-proline (11.5 mg, 20 molpercent), aryl (or heteroaryl) bromide (1 or 3,0.50 mmol), potassium iodide (KI) (249 mg, 0.75 mmol), and EtOH(1.5 mL) under nitrogen atmosphere. The Schlenk tube was sealedwith a teflon valve, and then the reaction mixture was stirred at110C for a period (the reaction progress was monitored by GCanalysis). After the reaction was completed, GC yield of high volatileproduct was determined using an appropriate internal standard(chlorobenzene or 1-chloro-4-methylbenzene) or the solvent wasremoved under reduced pressure. The residue obtained was puri-fied via silica gel chromatography (eluent: petroleum ether/ethylacetate = 10/1) to afford aryl iodides 2a–2o or heteroaryl iodides4a–4g.
With copper(l) iodide; caesium carbonate; dimethylbiguanide; In N,N-dimethyl-formamide; at 20 - 110℃; for 8.16667h;
General procedure: A 25 mL flask with a magnetic stirring bar was charged with CuI(9.6 mg, 0.05 mmol), metformin (0.1 mmol), Cs2CO3 (652 mg,2.0 mmol), imidazole (1.0 mmol), an aryl halide (1.1 mmol), andDMF (5 mL). The mixture was stirred for 10 min at room temperature,and then heated to 110?C for the appropriate amount of time(see Table 2). The progress of the reaction was monitored by TLC.After completion of the reaction, the mixture was extracted with EtOAc (5 1 mL) and the organic phase separated and evaporated. Further purification by column chromatography gave the desired coupled product.
95%
With copper(I) oxide; caesium carbonate; In N,N-dimethyl-formamide; at 120℃; for 12h;
General procedure: A 10-mL vial was charged with aryl halide (0.5 mmol), Cs2CO3 (1 mmol), Cu2O (0.05 mmol), N-containing heterocycles (0.75 mmol), DMF (1 mL), and a magnetic stir bar. The mixture was stirred at 120 °C (130 °C for entry 19). The reaction mixture was held at this temperature for 12 h (24 h for entry 18, 20, 21, and 25). After allowing the mixture to cool to room temperature, the reaction mixture was extracted with ethyl acetate (3 10 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate/petroleum ether as the eluent) to provide the target products 3a?3t.
93%
With C40H34CuIN6O6; sodium hydroxide; In dimethyl sulfoxide; at 100℃; for 4h;Sealed tube;
General procedure: For the catalysis reaction, the catalyst C1 (12 mg,0.01 mmol), imidazole (1.0 mmol), aryl halide(1.0 mmol), NaOH (80 mg, 2.0 mmol), and dimethylsulfoxide (DMSO, 5 mL) were taken in a sealed tube. The reaction mixture was stirred at 100 °C for 4 h and then cooled to room temperature. After adding 5 mL of H2O, the solution was extracted with ethyl acetate. The organic layer was then dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure.The N-arylated product was finally obtained by columnchromatography on silica gel.
91%
With copper(l) iodide; 1,10-phenanthroline N-oxide; caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 22h;Inert atmosphere;
To the three-neck flask, CuI (19 mg, 0.1 mmol, 10 molpercent), 1,10-phenanthroline-N-oxide (39 mg, 0.2 mmol, 20 molpercent), Cs2CO3 (650 mg, 2.0mmol). The reaction flask was evacuated under argon. p-cyanoiodobenzene (229 mg, 1.0 mmol), imidazole (102 mg, 1.5 mmol) and DMF (2 ml) were added under argon atmosphere. The reaction was allowed to proceed at room temperature for 22 hours until the reaction starting material was completely reacted (TLC assay reaction was complete). After completion of the reaction, a brown oil was obtained which was diluted with ethyl acetate. The inorganic salt was removed by filtration and the solvent was removed by rotary evaporation. The residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate as eluant to give 1-(4-carbonitrilephenyl)imidazole as a white solid in 91percent yield.
96%Chromat.
With C16H12ClN3OPdS; potassium hydroxide; In dimethyl sulfoxide; at 110℃; for 10h;
General procedure: Arylhalide (1.0 mM), nitrogen-containing heterocycle (1.2 mM), KOH (2 mM), and the catalyst (0.75 Mpercent) were stirred in dimethyl sulfoxide (DMSO) (4 mL) at 110 °C for 10 h. After completion of the reaction, the mixture was cooled to room temperature, diluted with ethyl acetate (10 mL) and filtered. The filtrate was concentrated and the residue was purified by column chromatography on silica gel using hexane/ethyl acetate(70 : 30) as eluent to afford the desired product. The products have been characterized by 1H NMR spectroscopy.
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; benzene; at 100℃; for 12h;
A 100 mL flask was charged with Pd (PPh3)4 mg, 0.3 mmol, 0.03 equiv), 4-iodo-benzonitrile (2.3 g, 10 mmol, 1 equiv), benzene (10 mL), an aqueous solution of Na2C03 (10 mL of a 2.0 M solution) and <strong>[144432-85-9]3-chloro-4-fluorophenylboronic acid</strong> (1.94 g, 11.0 mmol, 1.1 equiv, dissolved in a minimum amount of ethanol). The flask was equipped with a reflux condenser, and then placed into a preheated 100 C bath. After stirring for 12 h, the mixture was cooled to room temperature, diluted (H20) and extracted (EtOAc). The organics were washed (1 x brine), dried (Na2S04) and concentrated under reduced pressure. Purification of the residue by flash chromatography (Si02, 10% EtOAc/Hexane) provided 2.0 g of the product as a white solid (8.7 mmol).
Manufacturing Example 62-1-1 4-((5-Chloro-furan-2-yl)-hydroxy-methyl)-benzonitrile ; To a mixture of 4-iodobenzonitrile (3.0 g, 13 mmol) and tetrahydrofuran (40 mL) was added dropwise isopropyl magnesium chloride (1-2 M diethyl ether solution, 11 mL, 11-22 mmol) at -78 C., which was stirred for 1 hour at 0 C. The reaction mixture was cooled to -78 C., <strong>[21508-19-0]5-chloro-2-furaldehyde</strong> (2.2 g, 17 mmol) was added at that temperature, and the temperature was gradually raised to 0 C. Following 30 minutes of stirring at 0 C., saturated aqueous ammonium chloride solution, water and ethyl acetate were added to extract the reaction mixture. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride, and the solvent was evaporated under a reduced pressure. Ethyl acetate was added to the residue, which was then filtered with NH silica gel. The filtrate was concentrated under a reduced pressure to obtain the title compound (3.2 g) as a crude product. This compound was used in the subsequent reaction without further purification.
Manufacturing Example 16-1: 4-((5-Chloro-furan-2-yl)-hydroxy-methyl)-benzonitrile To a solution of THF (40 mL) and 4-iodobenzonitrile (2.0 g) was added isopropylmagnesium chloride (2M, 6.1 mL) dropwise at -78C under a nitrogen atmosphere, which was stirred for 1 hour and 10 minutes at 0C. After cooling to 78C, <strong>[21508-19-0]5-chloro-2-furaldehyde</strong> (1.4 g) was added dropwise thereto, which was stirred for 15 minutes at room temperature. A saturated aqueous ammonium chloride solution was added at room temperature, and then extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered, after which the filtrate was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (heptane:ethyl acetate = 1:1) to obtain the titled compound(2.4 g). 1H-NMR spectrum (DMSO-d6) delta (ppm): 5.78 (1 H, d, J = 4.9 Hz), 6.28 (1 H, d, J = 3.3 Hz), 6.37 (1 H, d, J = 4.9 Hz), 6.39 (1 H, d, J = 3.3 Hz), 7.59 (2H, d, J = 8.4 Hz), 7.84 (2H, d, J = 8.4 Hz).
To a mixture of 4-iodobenzonitrile (3.0 g, 13 mmol) and tetrahydrofuran (40 mL) was added dropwise isopropyl magnesium chloride (1-2 M diethyl ether solution, 11 mL, 11-22 mmol) at -78 C., which was stirred for 1 hour at 0 C. The reaction mixture was cooled to -78 C., <strong>[21508-19-0]5-chloro-2-furaldehyde</strong> (2.2 g, 17 mmol) was added at that temperature, and the temperature was gradually raised to 0 C. Following 30 minutes of stirring at 0 C., saturated aqueous ammonium chloride solution, water and ethyl acetate were added to extract the reaction mixture. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride, and the solvent was evaporated under a reduced pressure. Ethyl acetate was added to the residue, which was then filtered with NH silica gel. The filtrate was concentrated under a reduced pressure to obtain the title compound (3.2 g) as a crude product. This compound was used in the subsequent reaction without further purification.
Step 1: 4-(2-methoxyacetoyl)benzonitrile/so-propyl magnesium chloride (2 M solution in THF; 3.0 mL; 6.0 mmol) was added to an ice- cooled solution of 4-iodobenzonitrile (1.2 g, 5.0 mmol) in anhydrous THF (10 mL). This solution was stirred at this temperature for 10 minutes and then added dropwise to a cooled (-78 C) solution of /V-2-dimethoxy-/V-methylacetamide (0.998 g, 7.50 mmol) in anhydrous THF (5 mL). The reaction mixture was stirred at this temperature for 1 hour and then stirred at RT for 1 hour. The reaction mixture was then treated with 10% aqueous potassium hydrogen sulfate solution and extracted with DCM. The organic phase was passed through a hydrophobic frit and evaporated under reduced pressure. The residue was purified by flash chromatography eluting with /'so-hexane/EtOAc (3:2) to afford the title compound. 1H NMR (CDCI3, 400 MHz) delta 8.06- 8.04 (m, 2H), 7.80-7.77 (m, 2H), 4.67 (s, 2H), 3.50 (s, 3H).
With bis(di-tert-?butyl(4-?dimethylaminophenyl)?phosphine)?dichloropalladium(II); sodium carbonate; In 1,2-dimethoxyethane; water; at 80℃; for 4.0h;Inert atmosphere;
General procedure: Reactions were carried out in a Bohdan XT 24 position block using the appropriate halide indicated.2M Sodium carbonate (0.680 mL, 1.36 mmol) was added to a stirred mixture of <strong>[1207557-48-9]3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine</strong> (10, 151 mg, 0.62 mmol), the appropriate halide (0.74 mmol) and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (Pd(Amphos)Cl2) (26.3 mg, 0.04 mmol) in DME (4 mL) under nitrogen. The resulting mixture was stirred at 80 C for 4 h, allowed to cool, diluted with water (10 mL), extracted with EtOAc (2×25 mL) and the organic layer was evaporated to afford crude products. Unless otherwise stated the crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5 mu silica, 19 mm diameter, 100 mm length, 5-95% MeCN/1% NH3 in H2O).
(5S,8aR,9aS)-3,5,8a-trimethyl-6,7,8,8a,9,9a-hexahydronaphtho[2,3-b]furan-2(5H)-one[ No CAS ]
(5S,8aR,9aS)-3-(4-cyanobenzyl)-5,8a-dimethyl-6,7,8,8a,9,9a-hexahydronaphtho[2,3-b]furan-2(5H)-one[ No CAS ]
4-{(2S,3S,3a'R,5R,5S',8aS,8a'R,9aR,9a'R)-5,5',8a,8a'-tetramethyl-2'-oxo-3,3a',5,5',6,6',7,7',8,8a,8',8a',9,9a,9',9a'-hexadecahydro-1H,2'H-spiro[anthracene-2,3'-naphtho[2,3-b]furan]-3-yl}benzonitrile[ No CAS ]
(3aR,5S,8aR,9aR,E)-3-(4-cyanobenzylidene)-5,8a-dimethyl-3,3a,6,7,8,8a,9,9a-octahydronaphtho[2,3-b]furan-2(5H)-one[ No CAS ]
ethyl 1-(4-cyanophenyl)-1H-imidazole-4-carboxylate[ No CAS ]
ethyl 1-(4-cyanophenyl)-1H-imidazole-5-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
7%; 3%
With (1S,2S)-1-N,2-N-dimethylcyclohexane-1,2-diamine; copper(l) iodide; potassium carbonate; In 1,4-dioxane; at 95℃;
Step 1 ethyl 1-(4-cyanophenyl)-1H-imidazole-5-carboxylate A mixture of <strong>[23785-21-9]ethyl 1H-imidazole-4-carboxylate</strong> (10 g, 71.36 mmol, 1.00 equiv), CuI (2.7 g, 14.18 mmol, 0.20 equiv), potassium carbonate (30 g, 217.06 mmol, 3.02 equiv), 4-iodobenzonitrile (25 g, 109.16 mmol, 1.53 equiv) and (1S,2S)-1-N,2-N-dimethylcyclohexane-1,2-diamine (2.0 g, 14.06 mmol, 0.20 equiv) in 1,4-dioxane (200 mL) was stirred under nitrogen at 95 C. overnight. The reaction was cooled to room temperature and the solid material was removed by filtration. The filtrate was diluted with 800 mL of ethyl acetate then washed with 3*400 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with 1-3% of methanol in dichloromethane to give 450 mg (3%) of ethyl 1-(4-cyanophenyl)-1H-imidazole-5-carboxylate as a white solid. 1H-NMR (300 MHz, DMSO-d6): delta 8.19 (d, J=0.9 Hz, 2H), 7.84 (d, J=0.9 Hz, 2H), 4.15 (q, J=5.4 Hz, 2H), 1.16 (t, J=5.1 Hz, 3H) ppm. LCMS (method D, ESI): RT=1.19 min, m/z=242.0 [M+H]+ and 1.2 g (7%) of ethyl 1-(4-cyanophenyl)-1H-imidazole-4-carboxylate as a white solid. 1H-NMR (300 MHz, CDCl3): delta 7.90 (s, 1H), 7.82-7.76 (m, 3H), 7.50-7.47 (m, 2H), 4.24 (q, J=7.2 Hz, 2H), 1.28 (t, J=7.2 Hz, 3H) ppm. LCMS (method D, ESI): RT=1.16 min, m/z=242.0 [M+H]+.
2-(4'-cyanobiphenyl-2-yl)-1-methyl-1H-benzoimidazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
42%
With [ruthenium(II)(eta6-1-methyl-4-isopropyl-benzene)(chloride)(mu-chloride)]2; potassium carbonate; triphenylphosphine; In benzene; at 150℃; for 24h;Sealed tube;
General procedure: In a 30-mL sealed tube, <strong>[2622-63-1]1-methyl-2-phenylbenzimidazole</strong> (1, 0.25mmol), [RuCl2(p-cymene)]2 (0.0125 mmol), Ph3P (0.075 mmol),K2CO3 (0.50 mmol), and iodoarene (0.25 mmol) were combined inanhydrous benzene (2 mL) under air. The mixture was then stirredat 150 °C for 24 h. The mixture was cooled to r.t., diluted with EtOAc, and filtered through a small pad of Celite. The filtrate was concentrated in vacuo and purified by flash chromatography (silicagel, EtOAc?hexane) to give the analytically pure 2-(biphenyl-2-yl)benzimidazoles.
With trifluorormethanesulfonic acid; palladium diacetate; 2-(3,5-dimethyl-1H-pyrazol-1-yl)pyridine; In water; at 60℃; for 6h;
General procedure: To a mixture of arylboronic acid (1.2 mmol), nitrile (1.0 mmol), Pd(OAc)2 (4 mol%)and L1 (4 mol%), H2O (1.2 mL) and triflic acid (0.4 mL) were added and stirred at 60 Cunder air for desired time (TLC monitoring). Then the reaction mixture was neutralized withsaturated NaHCO3 solution and extracted with ether. The combined ether solution waswashed with brine, dried by Na2SO4 and concentrated. The residue was purified by flashcolumn chromatography on silica gel using petroleum ether/cetone or petroleum ether/DCMas eluent to give the desired product.
4-(2-methylpyrrolo[2,3-b]pyridin-1-yl)benzonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
0.3 g
With potassium phosphate; copper(l) iodide; trans-1,2-Diaminocyclohexane; In 1,4-dioxane; at 110℃; for 38h;Inert atmosphere;
Synth es is of 4-(2-Meth yl-pyrrolo[2,3-b]pyridin-1-yl)-benzonitrile (LXVI): To a degassed mixture of crude compound LXV (0.35 g), 4-iodobenzene (0.606 g, 2.64 mmol), and potass ium phosphate (0.955 g, 4.50 mmol) in 1 ,4-dioxane (20 mL) were added copper(I) 15 iodide (0.018 g, 0.132 mmol) and trans-(+/-)-1 ,2-cyclohexanediamine (0.015 g, 0.132 mmol). The reaction mixture was then heated at 110 C for 38 h, after w hich it was allow ed to cool to room temperature. The reaction mixture was filtered through celite bed and the filtrate w as condensed in vacuo. The remaining crude product mixture was purified by column chromatography on s ilica gel (100-200 mesh) using 30% ethyl acetate in hexanes as the 20 eluent to afford LXVI (0.300 g, 43% after two s teps) as an off-white solid.1H NM R (400 MHz, CDCl3): delta 8.20 (dd, J= 4.8, 1.5 Hz, 1H ), 7.85-7.83 (m, 3H), 7.59-7.56 (m, 2H), 7.11 - 7.07 (m, 1 H), 6.39 (s, 1 H), 2.38 (s, 3H); MS (ESI, positive mode) m/z 234 (MH+).
4-(6-bromo-2-methylindol-1-yl)benzonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
44%
Synthesis of 4-(6-Bromo-2-methyl-indol-1-yl)-benzonitrile (CXXXIV): To a solution of CXXXIII (1.0 g, 4.70 mmol) in 1,4-dioxane (50 mL) was added potassium phosphate (2.98 g, 0.044 mol) and 4-iodo-benzonitrile (2.1 g, 0.010 mol). The mixture was sparged with nitrogen gas for 0.5 h at room temperature. Then copper(I) iodide (0.44 g, 0.230 mmol) and 20 trans-(+/-)-1,2-diaminocyclohexane (0.054 g, 0.470 mmol) were added to the flask. The resultant reaction mixture was heated at 130 C for 48 h. After cooling to room temperature, the reaction mixture was filtered through a bed of celite and the filter pad was washed with ethyl acetate. The filtrate was concentrated under reduced pressure and the remaining crude 197 of 363 {//-- DRAFT --//4069/3020WO/00228726/v2} 4069.3020 WO product mixture was purified by column chromatography on (100-200 mesh) silica gel, using 5% ethyl aceate in hexanes to afford CXXXIV (0.65 g, 44%) as an off-white solid.1H NMR (400 MHz, CDCl3): delta 7.85 (d, J= 8.3 Hz, 2H), 7.4-7.45 (m, 2H), 7.42-7.39 (m, 1H), 7.24-7.22 (m, 2H), 6.41 (s, 1H), 2.29 (s, 3H).
4-(2-methylpyrrolo[3,2-b]pyridin-1-yl)benzonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
0.4 g
Synth es is of 4-(2-Meth yl-pyrrolo[3,2-b]pyridin-1-yl)-benzonitrile (XXI): In a s ealed tube, a mixture of copper (I) iodide (43 mg, 0.226 mmol), compound X X (0.600 g, 4.53 mmol) and potass ium phosphate (1.60 g, 7.70 mmol) in 1 ,4-dioxane (20 mL) w as sparged with nitrogen gas for 0.5 h. Then trans-(+/-)-1 ,2-cyclohexanediamine (26 mg, 0.226 mmol) and 4-iodo- benzonitrile (1.00 g, 4.53 mmol) where then added to the flask at room temperature and the 30 resulting reaction mixture was heated at 110 oC for 38 h. After cooling to room temperature, the reaction mixture was filtered through celite and the filter pad w as washed with ethyl acetate. The filtrate was concentrated to afford the crude product mixture. The crude was purified by column chromatography on silica gel (100-200 mesh) using 30% ethyl acetate in hexane as the eluant to obtain product XXI (0.4 g) as an off-white solid. 1H NMR (400 MHz, 114 of 363 {//-- DRAFT --//4069/3020WO/00228726/v2} 4069.3020 WO CDCl3): delta 8.45 (dd, J= 5.2, 1 Hz, 1H), 7.93 (d, J= 8.6 Hz, 2H), 7.60 (d, J= 8.2 Hz, 1H), 7.52 (d, J= 8.5 Hz, 2H), 7.21 (dd, J= 8.3, 5.2 Hz, 1H), 6.94 (s, 1H), 2.43 (s, 3H), MS (ESI, positive mode) m/z 234 (MH+).
With palladium diacetate; potassium carbonate; triphenylphosphine; In N,N-dimethyl-formamide; at 20 - 90℃; under 750.075 Torr; for 16h;Inert atmosphere;
General procedure: A mixture of Pd(OAc)2 (4.5 mg, 0.02 mmol), PPh3 (11.2 mg, 0.04 mmol), iodobenzene (1a) (82 mg, 0.4mmol), <strong>[936-59-4]3-chloropropiophenone</strong> (2a) (87 mg, 0.5 mmol), and K2CO3 (166 mg, 1.2 mmol) in DMF (2.5 mL) was stirred under a N2 atmosphere at room temperature for 10 min, and then heated at 90 C for 16 h. The reaction was then cooled to ambient temperature and diluted with CH2Cl2 (10 mL) before being filtered through a short pad of silica gel. The silica pad was rinsed with DCM (5 mL), and the combined filtrates were washed with brine (15 mL), dried over anhydrous Na2SO4. The solvent was then removed under reduced pressure to give the crude product as a residue, which was purified by silica gel column chromatography eluting with a mixture of petroleum ether (60-90 C)/EtOAc (v/v = 30:1).
With tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate; In tetrahydrofuran; for 1h;Reflux; Inert atmosphere;
To a solution of 1 -methylhomopiperazine (955 mg, 8.36 mmol) in THF (17 mL) was added Pd2(dba)3 (957 mg, 1 .05 mmol), BINAP (1 .302 g, 2.09 mmol), NaOf-Bu (938 mg, 9.76 mmol) and 4-iodobenzonitrile (1 .596 g, 6.97 mmol). The reaction mixture was stirred under reflux for 1 h. After cooling, the mixture was diluted with Et20 (200 mL), filtered and evaporated. The crude product was purified by column chromatography on silica gel (0/95/0 to 14.9/85/0.1 MeOH/DCM/NH4OH). Evaporation of the collected fractions yielded the title compound as a beige solid (915 mg, 61 % yield). H NMR (400 MHz, CDCI3) delta 7.44 (d, 2H), 6.63 (d, 2H), 3.59 (t, 2H), 3.49 (t, 2H), 2.69 (m, 2H), 2.55 (m, 2H), 2.37 (s, 3H), 2.00 (quad, 2H); HPLC: condition A, RT = 4.48 min, 95.0% homogeneity.
With tert.-butylhydroperoxide; copper(l) iodide; In N,N-dimethyl-formamide; at 130℃; for 48h;
General procedure: To a 25 mL round flask was added the mixture of boronic acid (1) (0.3 mmol), ethyl2-cyano-3-ethoxyacrylate (2a, 0.6 mmol), CuI (0.3 mmol), t-BuOOH (0.6 mmol) in DMF (2 mL)successively. The mixture was stirred at 130 C for 24 h under air. After the reaction was completed, themixture was cooled to room temperature, diluted with water (15 mL) and then extracted withdichloromethane (5 mL × 3). The organic extract was washed with H2O (10 mL × 3) and dried overanhydrous Na2SO4. After removal of the CH2Cl2 in vacuum, the crude product thus obtained was purified bycolumn chromatography on silica gel using petroleum ether/ethyl acetate as eluent to give the desired product3
3,6-bis(4-iodophenyl)-2,5-dihydropyrrolo[3,4-c]pyrrole-1,4-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
38%
With iron(III) chloride; sodium tert-pentoxide; at 50 - 120℃;
General procedure: A mixture of sodium (2.30 g, 100 mmol), t-amyl alcohol (50 mL) and catalytic amount of FeCl3 were added into a three-necked flask under air. After being stirred vigorously at 100 C for 1 h, the mixture was cooled to 50 C, 3 (40 mmol) was added. Then the mixture was heated to 100 C, <strong>[924-88-9]diisopropyl succinate</strong> (4.00 g, 40 mmol) in t-amyl alcohol (20 mL) was added dropwise over 2 h. Subsequently, the resulting suspension was kept for 3 h at 120 C, and cooled to room temperature. Glacial acetic acid was slowly added till pH was 7.0, followed by methanol and water (1:2, v:v,100 mL) added, the mixture was heated under reflux for 2 h. After cooling filtration and dried, the corresponding product was obtained. The product (2) was used without further purification.
With copper(l) iodide; ethylenediamine; sodium t-butanolate; In toluene; at 100℃; for 4.0h;
General procedure: CuI (10mol%) and EDA (10mol%) were added to a mixtureof O-alkyl carbamate (1mmol), NaOtBu (1.5mmol) and aryl halide (1mmol) in 2mL toluene and the mixture wasstirred for the appropriate time, which was determined byTLC monitoring, at 100C. After completion of the reaction,the catalyst was removed by filtration and 20mL H2Owas added to the filtrate. The resultant mixture was extractedwith CHCl3.Then the organic phase was washed with water(2 × 10mL) and dried over anhydrous Na2SO4.After evaporationof CHCl3under reduced pressure, the correspondingcrude product was purified by flash chromatography to givethe desired pure cross-coupling product in good to excellentyield. In the case of using arylboronic acids as couplingpartners, Cu(OAc)2 was employed instead of CuI.
With copper(l) iodide; cesium fluoride; In tetrahydrofuran; at 20℃; for 24h;Sealed tube;
A sealed tube was charged with 4-iodobenzonitrile (1.0 g, 4.4 mmol), <strong>[1192-07-0]isoxazolidin-3-one</strong> (1 .2 equiv.; 0.46 g, 5.2 mmol), dimethylethylenediamine (0.1 equiv., 0.47 mL, 0.44 mmol), cesium fluoride (2.5 equiv., 1.66 g, 10.9 mmol), copper iodide (0.05 equiv., 0.04 g, 0.20 mmol), tetrahydrofuran (8 imL) and the reaction contents were stirred at room temperature for 24 hours. The reaction contents were diluted with ethyl acetate and a saturated aqueous ammonium chloride solution. The layers were separated and the organic fraction was washed with water, dried over sodium sulfate, and concentrated under reduced pressure. The crude residue was purified by combiflash chromatography over silica gel (cyclohexane:EtOAc eluent gradient 9:1 to 1 :9) to afford 0.82 g (50% yield) of the title compound as an amorphous brown solid. (0614) LC/MS (Method A) retention time = 0.72 minutes, 188 (M+H)+. (0615) NMR (400 MHz, CDCIs) delta ppm: 7.83 (d, 2H), 7.65 (d, 2H), 4.59 (t, 2H), 3.07 (t, 2H), 3.30 (0616) (m, 2H).
4-(1,1-dioxo-1,2-thiazolidin-2-yl)benzonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With copper(l) iodide; cesium fluoride; In tetrahydrofuran; at 20℃; for 24h;Sealed tube;
A sealed tube was charged with 4-iodobenzonitrile (0.50 g, 2.2 mmol), 1 ,2-thiazolidine 1 , 1- dioxide (1.2 equiv.; 0.32 g, 2.6 mmol), dimethylethylenediamine (0.1 equiv., 0.23 mL, 0.22 mmol), cesium fluoride (2.5 equiv., 0.83 g, 5.47 mmol), copper iodide (0.05 equiv., 0.02 g, 0.10 mmol), tetrahydrofuran (4.7 mL) and the reaction contents were stirred at room temperature for 24 hours. The reaction contents were diluted with ethyl acetate and a saturated aqueous ammonium chloride solution. The layers were separated and the organic fraction was washed with water, dried over sodium sulfate, and concentrated under reduced pressure. The corresponding crude yellow oil (449 mg) was taken up in the next step without additional purification or characterization. (0600) NMR (400 MHz, CDCIs) delta ppm: 7.85 (d, 2H), 7.30 (d, 2H), 3.82 (t, 2H), 3.28 (t, 2H), 3.30 (m, 2H).
N-(5-(tert-butyl)-1,2,4-thiadiazol-2-yl)-4-cyanobenzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95%
With palladium diacetate; triethylamine; triphenylphosphine; In N,N-dimethyl-formamide; at 70℃;Inert atmosphere; Reflux;
General procedure: In a typical experiment Pd(OAc)2 (5.6mg, 0.025mmol), triphenylphosphine (13.1mg, 0.05mmol), iodobenzene (1) (or an other iodoaromatics, 2-18) (1.0mmol), and 2-amino-1,3,4-thiadiazol (a) (or its 5-substituted derivatives, b or c, or 2-amino-1,3-thiazole, d) (121.4mg, 1.2mmol) and triethylamine (0.5mL) were dissolved in DMF (10mL) under argon in a 100mL three-necked flask equipped with reflux condenser connected to a balloon filled with argon. The atmosphere was changed to carbon monoxide. The reaction was conducted for the given reaction time upon stirring at 70C and analyzed by TLC and GC-MS. The cooled reaction mixture was then concentrated and evaporated to dryness under reduced pressure. (0025) Method A. (2a, 14a, 1d-8d, 10d, 14d-16d): The residue was dissolved in chloroform (15mL) and washed three times with water (30mL). The organic phase was dried over Na2SO4, filtered and evaporated under reduced pressure to a solid material. Aforesaid compounds were subjected to column chromatography (Silicagel 60 (Merck), 0.063-0.200mm), EtOAc/CHCl3 eluent mixtures (the exact ratios are specified in Characterization for each compound; isolated yields are not optimized). (0026) Method B. (1a, 3a-13a, 15a-17a, 1b, 2b, 13b, 1c, 2c, 9d, 11d-13d, 17d): Toluene (15mL) was added to the residue, the insoluble material (product) was filtered, washed with water on the filter and dried. The off-white powder-like material was dissolved in methanol, the palladium-black was filtered off and methanol was evaporated.
4-((5-bromo-2-nitropyridin-3-yl)amino)benzonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
78.6%
Palladium acetate (0.1541 g, 0.69 mmol) and 4,5-bisdiphenylphosphine-9,9-dimethylxanthene were weighed out(Xantphos, 0.3977 g, 0.69 mmol) was added to a flask, dissolved with 20 mL of dioxane, and stirred at room temperature for 30 minutes.Weighed iodobenzonitrile (3.3g, 14.4mmol) into the flask, stirred for 15 minutes, added cesium carbonate (6.7g, 20.6mmol) and compound 3 (3.0g, 13.8mmol) into the flask under nitrogen protection. ,The reaction was stirred for 12 hours in a 100C oil bath. Filter to remove insolubles from the reaction solution.The filtrate was mixed with silica gel and ethyl acetate:petroleum ether=1:5 column chromatography to remove iodobenzonitrileThe crude product was separated by column chromatography on ethyl acetate. Recrystallization, yellow solid 4, yield: 78.6%
4-(4-methyl-2-phenylpiperazin-1-yl)benzonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)[2-(2-aminoethylphenyl)]palladium(II) dichloromethane; caesium carbonate; at 100℃; for 16h;Inert atmosphere;
(0667) A mixture of 4-iodobenzonitrile (300 mg, 1.31 mmol), <strong>[5271-27-2]1-methyl-3-phenylpiperazine</strong> (346 mg, 1.96 mmol), cesium carbonate (1.28 g, 3.93 mmol) and chloro(2-dicyclohexylphosphino- 2',6'-dimethoxy-1,1'-biphenyl)[2-(2-aminoethylphenyl)]palladium(II) dichloromethane adduct (176 mg, 0.262 mmol) in tert-amyl alcohol (5 mL) was stirred at 100 °C for 16 h under N2. After cooling to ambient temperature, the mixture was concentrated under reduced pressure to give a residue, which was diluted with H2O (10 mL). The water layer was extracted with EtOAc (20 mL x 2). The collected organic layers were washed with brine (10 mL) and dried over anhydrous Na2SO4. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 065percent EA/PE gradient (at) 40 mL/min) to give 4-(4-methyl-2- phenylpiperazin-1-yl)benzonitrile as an oil. ESI-MS m/z [M+H]+: 277.9.
With nickel(II) acetate tetrahydrate; triethylamine; In 1,4-dioxane; at 100℃; under 1500.15 Torr; for 4h;
General procedure: A mixture of aryl iodide (2 mmol), aryl alkyne (2.4 mmol), Ni(OAc) 2 (10 mol %), Et3N (6 mmol) and 1,4-dioxane (15 mL) were charged into the reactor (steel bomb). The reactor was closed and pressurized to ~2bar CO and then stirred at 100 C for 4 h. The reaction Progress was monitored by TLC. The reaction mixture was cooled to room temperature, before being filtered through a pad of Celite. The filtrate was concentrated and purified by silica gel with a mixture of hexane and ethyl acetate to give the pure product. For all examples, reactions were performed on 100 mg scale of corresponding aryl iodides.
With N-chloro-succinimide; silver(I) nitrite; In acetonitrile; at 20℃; for 6h;Sealed tube;
<strong>[766-99-4]4-iodophenylacetylene</strong> 114 mg (0.5 mmol), silver nitrite 115.5 mg (0.75 mmol), N-chlorosuccinimide133.5 mg (1.0 mmol) was sequentially added to a 10 mL pressure-resistant sealed container, and 5 mL of acetonitrile was further added.The mixture was stirred at room temperature, and the reaction was checked by TLC, and the reaction was completed in 6 hours.The reaction solution was diluted with 10 mL of dichloromethane, and filtered to give a clear liquid.Separation by column chromatography (extraction of petroleum ether/ethyl acetate in a volume ratio of 50:1)The eluate containing the desired product were collected and the solvent was evaporated to give 4-iodo-benzonitrile as a white solid 52.7mg (46% yield).
With (1,2-dimethoxyethane)dichloronickel(II); N,N,N,N,-tetramethylethylenediamine; (4,4'-di-tert-butyl-2,2'-dipyridyl)-bis-(2-phenylpyridine(-1H))-iridium(III) hexafluorophosphate; water; N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 80℃; under 760.051 Torr; for 24h;Schlenk technique; Sealed tube; Irradiation;
General procedure: Aryl-halide (0.2 mmol, 1 equiv.), Ir(dtbbpy)(ppy)2PF6 (1.8 mg, 0.002 mmol, 1 mol %), NiCl2.glyme (4.4mg, 0.02 mmol, 10 mol %), DMSO (2.0 mL) was added to a 10 mL schlenk flask equipped with a magnetic stirrer bar. This resulting mixture was sealed and degassed via vacuum evacuation and subsequent backfill with ethylene for three times. Then, N,N,N?,N?-tetramethylethylenediamine, TMEDA(60 muL, 2 equiv.), N,N-diisopropylethylamine, DIPEA (70 muL, 2 equiv.) and H2O (7.2 muL, 2 equiv.) were subsequently added in this order. The mixture was then irradiated with blue LED (2 meter strip, 18 W)with ethylene balloon for 24 hours at 80oC (Figure S1). The reaction was added water (30 mL) and extracted with ethyl acetate (10 mL) three times. Combined organic layer was successively washed with brine three times and dried over Na2SO4 and concentrated under reduced pressure. The residue was then subjected to flash column chromatography (hexane or hexane/ethyl acetate) to yield theproduct
1-((4-cyanophenyl)amino)cyclopentyl-1-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
57.5%
With copper(l) iodide; dimethylaminoacetic acid; potassium carbonate; triethylamine; In water; N,N-dimethyl-formamide; at 110℃;
Synthesis steps: 1-aminocyclopentane-1-carboxylic acid (5.0 g, 32.9 mmol) and 4-iodobenzonitrile (11.33 g, 49.5 mmol) were dissolved in DMF / H2O (60 mL, v / v = 5 / 1) To the solution, add K2CO3 (13.6g, 98.4mmol), Et3N (0.33g, 3.29mmol), CuI (1.25g, 6.56mmol) and N, N-dimethylglycine (6.56mmol), and the mixture is at 110 C After heating overnight and cooling to room temperature, the reaction mixture was diluted with H2O (500 mL) and the pH was adjusted to about 4.0 with 1.0 N aqueous HCl. It was extracted with EtOAc (150 mL x 2), and the combined organic layers were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained concentrate was separated by silica gel column chromatography (PE: EA: CH3COOH = 1.0: 1.0: 0.01) to obtain solid B-1.Yield: 57.5%;
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
For Research Only
110K+ Compounds
Competitive Price
1-2 Day Shipping
